Abstract Although there have been tremendous advances in the treatment of breast cancer over the last decade and mortality has been decreasing, this progress has been confined primarily to the subset of patients who overexpress ErbB2 and/or have expression of a hormone receptor. Triple negative breast cancer (TNBC) is the only subset of breast cancers for which there are no FDA-approved targeted therapies and clinicians are entirely reliant upon cytotoxic agents for tumor control. Clearly, there is a strong need for targeted and novel therapeutics against TNBC. We have developed a mechanistically novel c-Src/p38 inhibitor, UM-193, that is orally bioavailable and has potent in vivo anti-TNBC activity. However, single-agent targeted therapies have been demonstrated to be often prone to resistance and thus, rational combinations are sought. Indeed, while we have achieved potent single agent activity without evidence of in vivo resistance, we have been able to produce acquired in vitro resistance to UM-193. Combination of targeted therapies is a validated strategy to increase efficacy to a single agent and thereby prevent resistance from emerging. On the basis of our preliminary data, we hypothesize that combination of UM-193 with trametinib, an FDA-approved MEK inhibitor, will exhibit enhanced anti-TNBC activity. Our hypotheses are supported by the role of c-Src and the MEK/ERK axis in TNBCs and the hyperactivation of the MEK/ERK pathway in TNBC cell lines made resistant in our lab to UM-193. To assess these hypotheses, we propose to use innovative and advanced in vitro and in vivo models of TNBC. Specifically, using our unique collection of already characterized low-passage TNBC PDXs, we will determine, using single cell analyses and bioplex signaling, which biomarkers predict patient response and resistance for future clinical trials.